Dengue

Dengue

James Whitehorn† and Jeremy Farrar‡*

†London School of Hygiene and Tropical Medicine, London, UK, and ‡Hospital for TropicalDiseases, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme,Ho Chi Minh City, Vietnam

Introduction: Dengue is a vector-borne viral infection that endangers an

estimated 2.5 billion people. Disease caused by dengue ranges from a relatively

minor febrile illness to a life-threatening condition characterized by extensive

capillary leak. A greater understanding of dengue has the potential to improve

both the clinical management of individual cases and the control of the disease.

Sources of data: We searched the available literature using PubMed, Embase

and Web of Science for relevant articles and abstracts.

Areas of agreement: Addressing our gaps in the understanding of disease

pathogenesis and improving our knowledge of dengue virus biology are necessary

in order to develop tools to effectively control, diagnose and treat the disease.

Areas of controversy: The pathogenesis of dengue is multifactorial and depends

on both host and virus factors. A more integrated understanding of disease

pathogenesis is necessary.

Areas timely for developing research: There are many questions related to disease

pathogenesis, development of diagnostics, drug and vaccine development and

individual case management that need addressing if the disease is to be

successfully tackled.

Keywords: dengue/dengue haemorrhagic fever/dengue shock syndrome/pathogenesis/vaccine/drug development

Introduction

Dengue is a viral infection transmitted by Aedes mosquitoes.1 Dengue isa flavivirus with four different antigenically distinct serotypes(DENV1-4).2,3 It is a rapidly growing health problem with an estimated2.5 billion people at risk, mainly in countries of south and south-eastAsia, the Caribbean, Central and South America, and more recently inAfrica.4,5 The spread of dengue is thought to be due to a combination offactors: increased urbanization, population growth, migration and inter-national travel and the difficulties of effective vector control.6 Climatechange may be a contributing factor in the global spread of dengue.7

British Medical Bulletin 2010; 95: 161–173

DOI:10.1093/bmb/ldq019

& The Author 2010. Published by Oxford University Press. All rights reserved.

For Permissions, please e-mail: [email protected]

Accepted: June 14, 2010

*Correspondence address.

Hospital for Tropical

Diseases, Oxford

University Clinical

Research Unit, Wellcome

Trust Major Overseas

Programme, Ho Chi Minh

City, Vietnam. E-mail:

[email protected]

Published Online July 8, 2010

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It is estimated that there are between 50 and 100 million cases of dengueeach year, of which �500 000 are severe life-threatening infections.8

There have been numerous urban outbreaks of dengue with significanthealth and economic impacts.9–11 Studies in Thailand and Brazil haveshown that the social and economic impact is equivalent to that ofmalaria in these countries.12,13 However, globally dengue research hasnot received the same level of funding as other tropical infectious dis-eases.8 There are currently no available drugs and no licensed vaccine,and diagnosis in endemic areas is largely clinical.14 Dengue also poses arisk to those who travel to endemic areas and is increasingly beingreported in travellers returning from trips to endemic countries.15

Dengue viruses cause a variety of clinical syndromes ranging fromasymptomatic infection to a self-limiting febrile illness to severe dengue,a life-threatening condition characterized by increased capillary per-meability and shock.16–18 There are concerns that the old WHOdefinitions of dengue that are still in widespread use may lead to under-diagnosis of severe dengue.19 In clinically apparent dengue infectionsymptoms develop after an incubation period of 4–7 days with an abruptonset of fevers often accompanied by headache with severe retro-orbitalpain.20,21 Some patients develop severe arthralgia, explaining the histori-cal name of break-bone fever.22 Early in the illness the skin may appearflushed, with petechiae appearing during the ‘critical phase’ and amacular rash appearing in early convalescence. Even after uncomplicateddengue recovery may be complicated by fatigue and depression.Thrombocytopenia is almost universal in dengue infection and minorbleeding from skin and mucosal surfaces may be seen in uncomplicatedinfections—this can be severe in patients with peptic ulcer disease.23

Biochemical hepatitis is frequently seen in dengue infection, but severeliver pathology, encephalitis and renal dysfunction are relatively rare.21,24

Data from Taiwan show differences in disease manifestations betweenadults and children observed during an outbreak in 2002.25 Arthralgia,headache, gastrointestinal bleeding and significantly severe dengue weremore common in adult patients. The reasons for these differences are notclear but could reflect differences in the host response to infection.Significant and disabling fatigue has been described after recovery fromdengue.26 It is thought that host factors may contribute to the develop-ment of this condition. Vertical transmission of dengue can occur if infec-tion of the mother occurs within 8 days of delivery.27 The WHO haverecently published new guidelines on dengue management.28 The newguidelines indicate that disease caused by dengue encompasses a wideclinical spectrum and that the previously used classifications for severedengue were not always helpful. Dengue is classified in the new systemas either uncomplicated or severe.28 Severe disease is characterizedby plasma leak, haemorrhage and organ impairment. Recognizing the

J. Whitehorn and J. Farrar

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warning signs for severe disease is important for successful clinicalmanagement. Warning signs include abdominal pain, evidence of fluidaccumulation, hepatomegaly and increases in haematocrit accompaniedby a fall in the platelet count.28 The mechanisms that lead to severedengue are not completely understood although various hypotheses exist.Perhaps the most widely accepted hypothesis explaining the developmentof severe dengue is that of antibody-mediated immune enhancement,where antibodies developed to a previous infection lead to enhanced viraluptake with a new infection of a different serotype.29,30 This and otherhypotheses will be discussed in a later section of this review.

Sources of data

We searched the available literature up to April 2010 using PubMed, Webof Science and Embase and making use of the following terms: ‘dengue’;‘dengue fever’; ‘dengue haemorrhagic fever (DHF)’; and ‘dengue viruses’.

Areas of agreement

As dengue has emerged as a global health threat, it has receivedincreased attention from the international public health community.14

Essentially areas of agreement are based around addressing the lack ofeffective diagnostic and therapeutic options, improving clinical care ofaffected patients and developing tools to prevent dengue infection.

Areas of controversy

Is the virus itself or the host response to infection the main cause of severe disease?

The four serotypes of dengue can be further classified into differentgenotypes based on nucleotide variation.31 Different genotypes havebeen associated with different levels of virulence.32,33 It appears thatthe virus may evolve during epidemics to cause more severe disease asseen in disease outbreaks in Cuba and Australia.34,35 It has beensuggested that structural differences in strains of the virus lead to dif-fering abilities to infect different cell types or cause severe disease.36,37

However, given that only a small percentage of patients infected withdengue develop severe disease, it is clear that host factors have a majorrole to play in dengue pathogenesis.31

Many of the clinical features of dengue infection may be due to thepatients’ immune response. The increased vascular permeability seen in

Dengue

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dengue is associated with high levels of cytokines including tumournecrosis factor alpha (TNF-a), interferon gamma (IFN-g), interleukin 6(IL-6) and interleukin 2 (IL-2).38,39 However, it is important to notethat these cytokines are elevated in many diseases, yet dengue is a veryspecific clinical entity. Therefore the clinical features of dengue couldbe due to a specific constellation of these cytokines or a more complexinteraction between host and virus that is yet to be characterized.Polymorphisms in TNF-a are associated with more severe disease.40

Various other genetic factors have been associated with more severedisease: for example, polymorphisms in the vitamin D receptor gene,the mannose-binding lectin gene, and various HLA class I and IIalleles.41–44 However, none of these studies have been large enough toindicate a clear association and the question of host susceptibilityremains unanswered. Cytokine dysregulation and endothelial injurycontribute to the pathogenesis of yellow fever, another flavivirus.45

The pathophysiology of severe yellow fever infection remains unclear,but given similarities with severe dengue, there may be an overlap inthe host and virus determinants of susceptibility.

Is the hypothesis of antibody-mediated enhancement sufficient to explain thedevelopment of severe disease?

Epidemiological studies have shown that severe disease is more com-monly seen after secondary infections.46 Infection with one serotype isthought to result in brief protection against all serotypes. As the levelsof neutralizing antibodies fall over time the non-neutralizing or sub-neutralizing antibodies form complexes with the new infecting virusand these complexes are taken up by Fc-receptor bearing cells. Thisresults in increased uptake of virus, increased replication and viralload, and hence a postulated increased likelihood of complications.30

This phenomenon explains the severe disease observed in infants agedbetween 6 and 9 months, where the low non-neutralizing levels ofmaternally derived antibodies are thought to play a crucial role in thedevelopment of severe disease.47,48 These observations have led to con-cerns that a vaccine may potentially result in more severe disease bypriming the immune system and putting individuals at risk when theyare subsequently infected. These fears are ungrounded if such a vaccineproduces long-term neutralizing protection to all four serotypes andthose serotypes do not change over time.3 However, severe disease canoccur in primary infections and most secondary infections do not resultin severe disease indicating that other factors contribute.49–51 Directevidence for antibody-dependent enhancement (ADE) contributing tothe development of severe disease in humans has been difficult to



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demonstrate, although recent work in infants and elegant in vitro andclinical studies have started to yield crucial insights into how ADE maycontribute to pathogenesis.51,52,53

The pathogenesis of dengue is complex and multifactorial. No hypoth-esis in isolation is sufficient to explain the development of severe disease.It is the interplay between virus factors and genetically determined hostfactors that determine the disease outcome in the individual patient.

Growing points—areas timely for developing research

Increased understanding of dengue pathogenesis

As discussed above the mechanisms that lead to severe dengue are incom-pletely understood. A greater and clearer understanding of disease patho-genesis including host genetics, virus biology and immunopathology,would help the development of targeted clinical interventions.14 Clarifyinghow dengue virus virulence varies between serotypes and evolves withinepidemics would be helpful. Do different serotypes vary in their tissuetropism thus explaining differences in disease severity? Elucidating howthe different factors within the immune system interact and contribute todisease development is essential. Too often research focuses on a singleaspect of the immune response, be it antibody-mediated enhancement,T and B cell responses or the role of complement when a more integratedview, including consideration of the virus, is required.31

Non structural protein-1 (NS1) is a glycoprotein secreted bydengue-infected cells. Early detection of NS1 has demonstrated efficacyas a diagnostic tool.54 Its role in dengue pathogenesis is unclear—defin-ing this role may lend weight to its use in diagnostics. It is possible thatit activates complement at endothelial surfaces thus contributing to thevascular leak that occurs in severe disease.55 Clarifying the events thatoccur at the endothelial surface in dengue infection would be a majoradvance—the development of a suitable animal model of dengue infec-tion would aid this progress.56

An increased understanding of genetic factors that contribute todisease development would help define more clearly populations atrisk. Within populations an increased understanding of differing sus-ceptibilities to disease development is necessary.31

Optimization of clinical management

The commonly used WHO guidelines for the management of denguewere developed after observations in children hospitalized in Bangkok

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in the 1960s with dengue.19 These guidelines have evolved over theyears and have been adopted into clinical practice in endemic areas. Anattempt to validate the WHO classifications for severe disease has beenrecently published.57 This study showed that while the WHO classifi-cations had good specificity for severe disease the sensitivity was lower.There is no doubt that the use of the guidelines have led to substantialmortality reductions, yet are guidelines originally developed for Thaichildren 40 years ago still applicable today or, for example, in theincreasing number of adult patients seen globally?19,58

One of the difficulties diagnosing DHF using the old WHO defi-nitions was that the criteria were too rigid.16 Studies have shown thatmany cases of dengue that resulted in shock or death did not meet theWHO case definitions.59,60 These problems have led to the develop-ment of the new WHO guidelines that categorize dengue cases intouncomplicated or severe.28 These guidelines emphasize the importanceof recognizing the warning signs of severe dengue—abdominal pain,vomiting, fluid accumulation, mucosal bleeding, lethargy or restlessness,hepatomegaly, rising haematocrit in conjunction with falling platelets.28

These 2009 WHO guidelines include a detailed description of the clinicalmanagement of dengue including an algorithm for the management(http://whqlibdoc.who.int/publications/2009/9789241547871_eng.pdf).A challenge is educating health-care workers about the new guidelinesand ensuring that they result in better clinical care.

The mortality in severe dengue remains significant particularly ininfants.50,61 In addition higher mortality rates are seen when denguenewly emerges in regions where there is less experience in clinical man-agement of cases, for example, as seen in the epidemics in India andBrazil.10,62 Fluid management in dengue is difficult—the balancebetween too much and too little is critical and getting it wrong can belife-threatening.63 Fluid resuscitation is not without risk and fluid over-load in the recovery phase can cause acute respiratory distress syn-drome.28 Fluid management in patients with co-morbidities orpregnancy is difficult and would benefit from further research.

It is likely that there is a significant unreported burden of mortalityin remote health facilities, where clinical management may be poor.Early and careful administration of parenteral fluids is life-saving insevere dengue. Ringer’s lactate has demonstrated efficacy for use indengue shock syndrome and dextran or starch have also been suggestedfor severe disease.64 Successful management of severe dengue requiresfavourable staff-to-patient ratios and the ability to closely monitorpatients.28 Unfortunately the use of parenteral fluids and the intensemonitoring that is required may not always be available and there is aneed for research on the use of oral rehydration therapy aimed at pre-venting the development of shock in severe dengue.14



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The endothelial leak seen in severe dengue is transient and if appro-priate supportive therapy is given during this period, mortality ratesare low.16 However, in the early stages of disease clinical features arenon-specific and are shared with other infectious aetiologies.61 Makinga diagnosis early in the disease would significantly aid clinical manage-ment. Additionally predicting which patients are at risk of severedisease would be a major advance. Traditionally diagnosis has reliedon serology, which can take time to give useful results, meaning thatdiagnosis is often retrospective.1 IgM against dengue can be detectedafter 5 days of fever—commercially available diagnostic kits based onELISA have been assessed.65 These have potential but have limitations,for example, the persistence of IgM in some patients in endemic areasmaking it difficult to diagnose an acute infection. The detection of thedengue protein NS1 also has proven use in diagnosis.54 Quantifyingthe titre of NS1 early in clinical illness may allow one to predict thoseat risk of developing severe disease.66 Real-time PCR is another poten-tial, highly sensitive diagnostic tool in dengue diagnosis.67 However,the cost of molecular tests such as PCR make it an impractical tool foruse in many settings where dengue is prevalent. A rapid sensitive testthat combines detection of NS1, IgG and IgM allowing diagnosis ofinfection throughout the illness course would be a major advance indengue diagnostics. The development of appropriate clinical algorithmsfor use in resource-limited settings in parallel to the development ofmolecular diagnostic tools is necessary if the burden of dengue is to beadequately dealt with. A study has demonstrated the potential use of adecision tree algorithm using simple clinical and haematological par-ameters.68 Testing the validity of such an algorithm in primary care set-tings have the potential to improve the triage and initial clinicalmanagement of patients with dengue. Detection of plasma leakagethrough serial ultrasound is a useful adjunctive tool in dengue diagno-sis and management, and yet it is unlikely to be of benefit in manyareas due to lack of availability.69 Identifying additional predictors ofdengue would be useful, but making these into diagnostic techniquesthat are practical in resource-limited settings is the challenge.70

Vaccine development

A vaccine against dengue would be a major advance in the control ofthe disease. In view of the potential risks of antibody-mediatedenhancement seen with heterotypic infections, a successful vaccinewould have to offer lasting protection against all four serotypes.2

Based on the success of vaccination against other flaviviruses, forexample, Japanese encephalitis and yellow fever, the development of a

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live attenuated vaccine had previously been the most promising pro-spect for vaccinologists.71 However despite encouraging results withmonovalent vaccines in clinical trials the development of a tetravalentformulation has proved problematic and development has been sus-pended.3,72–75 The leading vaccine candidate at present is a chimericvaccine—a recombinant clone based on yellow fever vaccine strainwith dengue virus membrane and envelope protein genes substitutedinto the construct.76,77 This chimeric vaccine has shown promise inPhase II clinical trials and appears safe and immunogenic. It is antici-pated that Phase III trials will start in the near future.

Despite promising progress there remain unanswered questions thatneed to be addressed and are potential areas for research. The lack of asuitable animal model of dengue infection hinders the transfer of lab-oratory findings into clinical practice.31 How do we quantify immuneprotection? Do tetravalent vaccine constructs hinder the developmentof immunity to individual serotypes? Could a dengue vaccine renderpopulations more vulnerable to severe infection, either throughantibody-mediated enhancement or via a mechanism similar to thatseen with vaccines against respiratory syncytial virus?78 How safe aredengue vaccines in different subsets of the population?3

In addition to the science of vaccine development and questionsregarding the safety and efficacy of individual vaccine candidates, thereneeds to be sustained co-ordination between different countries andvaccine developers if a vaccine is to be successfully developed.53,79

Anti-dengue drugs

A greater understanding of dengue virus biology has meant that targetswithin the lifecycle have been identified that could potentially be thesite of a therapeutic agent.80 The staggering success in developingdrugs against HIV is an example of how efficiently effective antiviralscan be developed given appropriate funding.

One potential mechanism of action of an anti-dengue drug is throughinhibition of viral entry. The fusion of the viral membrane with the hostmembrane is mediated by dengue virus E protein.81 Research has shownsome promising initial results in laboratory studies with an experimentalentry inhibitor—these findings could pave the way to the development ofsuccessful therapeutic agents.82 Other potential targets receiving researchattention are the viral proteins NS3 and NS5, which play an integral rolein genome replication—their protease domains could be target forprotease inhibitors.83,84 A computer program has been used to identifysuitable molecules that can ‘dock’ into the NS3 protease domain.85 Thechallenge is to bridge the gap between findings in the laboratory and the



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bedside; however, given the progress in our understanding of denguevirus biology, the future of drug development is encouraging. There arepotential therapeutic developments for the treatment of other flavivirusessuch as hepatitis C.86 In view of structural similarities between differentflaviviruses, these developments could be used in the field of dengue treat-ment. The complications of dengue occur as the virus is cleared from theblood, and so it is possible that an anti-dengue drug will have no ben-eficial role. As the severe manifestations of disease are in part due to theimmune response perhaps the development of an immunomodulatoryagent would be the best therapeutic strategy? Animal studies have shownthe protective effect of monoclonal antibodies against the NS1 protein ofWest Nile virus, and more recent work in mice has shown the therapeuticpotential of a monoclonal antibody directed against a structural epitopein an experimental DENV-1 infection.87,88

Vector control

In addition to vaccination, successful vector control would be a usefuladjunct to controlling dengue. Dengue is closely associated with Aedesaegypti—the global spread of dengue is related to changes in humanbehaviour, in particular the expansion of large urban centres, whichsupport the breeding of A. aegypti.6 Although vector control has pre-viously had success, the persistence of pockets of mosquitoes resultedin disease re-emergence.89 Studies have shown different efficiencies ofdengue transmission between different mosquito strains and differentserotypes of dengue.90,91 A greater understanding of the interactionsbetween mosquitoes and the different serotypes of dengue would giveus a greater understanding of transmission dynamics and would poten-tially lead to better prediction of epidemics, and thus better control ofthe disease. The development of genetically modified mosquitoes thatare less able to transmit dengue is a potential option for diseasecontrol. However, mathematical models have indicated that this strat-egy may select for greater disease virulence, suggesting that measuresthat increase mosquito mortality may be more effective.92 Transgenicmosquitoes are likely to be less reproductively fit—infection of trans-genic mosquitoes with the symbiont Wolbachia potentially confers areproductive advantage, thus allowing the establishment of transgenicsin the environment.93 Cyclopoid copepods are invertebrate predatorsof mosquito larvae. Introduction of copepods into water containers,the typical breeding site of Aedes, can have a major impact on mos-quito populations.94 The roll-out of larvicidal interventions requiresactive community involvement and the success of such measures woulddepend on imaginative public health engagement.94

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Conclusions

Successfully tackling the threat of dengue represents a major publichealth challenge for the twenty-first century. A co-ordinated multidisci-plinary approach is necessary. Major advances are possible provideddengue research receives the attention and funding its prevalencedeserves.

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